CN116406276A

CN116406276A - Cancer therapy using toll-like receptor agonists

Info

Publication number: CN116406276A
Application number: CN202180073044.5A
Authority: CN
Inventors: S·C·卡茨; B·F·考克斯; D·B·雅洛克
Original assignee: Tesalas Life Sciences
Current assignee: Tesalas Life Sciences
Priority date: 2020-09-22
Filing date: 2021-09-21
Publication date: 2023-07-07
Also published as: WO2022066673A1; EP4216930A1; CA3196274A1; JP2023542989A; KR20230123921A; AU2021347690A1; AU2021347690A9; US20230374523A1; DE112021004970T5; WO2022066673A9

Abstract

Embodiments of the present invention provide methods of treating cancer and methods of delivering toll-like receptor (TLR) agonists to solid tumors in the pancreas through the vasculature using localized regional therapy. In one aspect, the invention relates to a method of treating pancreatic cancer comprising administering a TLR agonist to the pancreas.

Description

Cancer therapy using toll-like receptor agonists

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional patent application No. 63/081,613, filed on 9/22 2020, which is incorporated herein by reference in its entirety.

Sequence listing

The present application contains a sequence listing submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy was created on 9 months and 16 days 2020, named a372-502_sl.txt, of size 484 bytes.

Technical Field

The present disclosure relates generally to methods of treating cancer and methods of delivering toll-like receptor (TLR) agonists to solid tumors in the pancreas through the vasculature using localized regional therapy.

Background

Cancer is a devastating disease involving the uninhibited growth of cells, which can lead to the growth of solid tumors in various organs such as the skin, liver and pancreas. The tumor may first be present in any number of organs, or may be the result of metastasis or diffusion from other parts.

Pancreatic cancer is the third leading cause of cancer death in the united states, with an estimated 55,000 people dying from pancreatic cancer in 2018. The 5-year survival rate of such cancers is only 7 to 8% due to a variety of factors including the advanced stage of the disease where initial diagnosis is frequent, the propensity of such cancers to metastasize, the resistance of the disease to chemotherapy and radiation therapy, and the complex microenvironment of pancreatic cancer tumors. Only 15 to 20% of patients are eligible for surgical removal of the primary tumor at diagnosis, as most patients were initially diagnosed with unresectable (metastatic or locally advanced) disease. Current standard of care for unresectable or metastatic pancreatic cancer is palliative systemic chemotherapy with gemcitabine (gemcitabine, gem) monotherapy, gemcitabine/albumin-conjugated paclitaxel (nab-paclitaxel) or folinic acid/fluorouracil (fluorouracil)/irinotecan/oxaliplatin (folfirininox). For patients with marginal resectable or locally advanced disease, combination regimens have been used to potentially convert some marginal resectable tumors and even some locally advanced tumors to resectable. In addition, the relatively poorly vascularized tumor microenvironment seen in most pancreatic cancers makes targeting and global arterial delivery of chemotherapeutic agents using conventional techniques challenging.

Furthermore, locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) is associated with rapid progression, resistance to conventional therapies, deterioration of quality of life, significant morbidity and high mortality. PDAC tumors are characterized by dense connective tissue-promoting hyperplastic matrix, lack of effector immune cells, making both drug delivery and stimulation of immune responses very challenging.

Thus, there remains a need in the art for a more accurate, better targeted method of delivering chemotherapy to treat solid tumors (e.g., pancreatic cancer) that addresses the limitations of the current technology.

Disclosure of Invention

The present invention relates to methods of treating cancer and methods of delivering TLR agonists to solid tumors in the pancreas through the vasculature using localized regional therapy.

In another aspect, the invention relates to a method of treating pancreatic cancer comprising administering a TLR agonist via retrograde venous infusion of the Pancreas (PRVI) via an intravascular device. According to another embodiment, the treatment of pancreatic cancer comprises administering a TLR agonist via Pancreatic Arterial Infusion (PAI) via an intravascular device.

In some embodiments, TLR agonists are administered by pressure-enabled drug delivery (PEDD), which includes administration of a therapeutic agent by a device (e.g., a catheter device) that generates, causes, and/or contributes to a net increase in fluid pressure within a blood vessel and/or target tissue or tumor.

In some embodiments, the TLR agonist is administered by a pressure-enabled device, e.g., a device that increases vascular pressure.

In some embodiments, the TLR agonist is a C class CpG oligodeoxynucleotide (CpG-C ODN).

In some embodiments, administering a TLR agonist to the pancreas via an intravascular device results in an increase in responsiveness to checkpoint inhibitor therapy in pancreatic cancer.

In some embodiments, the TLR agonist is a TLR9 agonist.

These and other objects, features and advantages of the exemplary embodiments of the present disclosure will become apparent upon reading the following detailed description of the exemplary embodiments of the present disclosure in conjunction with the accompanying paragraphs.

Drawings

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the disclosure.

FIG. 1 shows the structure of SD-101.

Figures 2A to 2B compare tumor volumes in murine models after systemic saline infusion, saline infusion via PRVI/PEDD, systemic SD-101 infusion and SD-101 infusion via PRVI/PEDD, and contain data and graphical forms, respectively.

Figures 3A to 3B compare tumor weights in murine models after systemic saline infusion, saline infusion via PRVI/PEDD, systemic SD-101 infusion and SD-101 infusion via PRVI/PEDD, and contain data and graphical forms, respectively.

FIG. 4 shows normalized labeled SD-101 signal intensity in porcine pancreas infused via PRVI, comparing local concentrations of SD-101 relative to adjacent non-target tissue within the pancreas (all data).

FIG. 5 shows normalized labeled SD-101 signal intensity in porcine pancreas infused via PRVI, comparing local concentrations of SD-101 relative to adjacent non-target tissue within the pancreas (outlier removal).

Fig. 6 shows the treated tissue volume of the SEAL device (all data) compared to the end hole catheter in a pig model.

Figure 7 shows the processed signal intensity (all data) of the SEAL device compared to the end hole catheter in the pig model.

Fig. 8 shows the treated tissue volume of the SEAL device (outlier data removed) compared to the end hole catheter in the pig model.

Fig. 9 shows the processed signal intensity (outlier data removed) of the SEAL device compared to the end hole catheter in the pig model.

Figures 10A to 10B show the distribution pattern of labeled SD-101 delivered to porcine tissue via a tip hole catheter and a SEAL device, respectively.

Fig. 11 shows the overall design of a pancreatic retrograde intravenous infusion (PRVI) study of PEDD using TLR9 agonist SD-101 for response rates of locally advanced PDAC patients to CPI.

Throughout the drawings, the same reference numerals and characters are used to denote like features, elements, components or portions of the illustrated embodiments unless otherwise specified. Furthermore, while the present disclosure will now be described in detail with reference to the drawings, the description is in connection with the illustrative embodiments and is not limited to the specific embodiments shown in the drawings and the accompanying paragraphs.

Detailed Description

The following description of the embodiments provides non-limiting representative examples of reference numerals to specifically describe features and teachings of various aspects of the invention. The described embodiments should be considered to be capable of being implemented separately or in combination with other embodiments from the description of the embodiments. Those of ordinary skill in the art who review the description of the embodiments will be able to learn and understand the various described aspects of the invention. The description of the embodiments should be taken as an aid to understanding the invention to the extent that other implementations are not specifically contemplated, but are within the knowledge of one skilled in the art after reading the description of the embodiments to be considered consistent with the application of the invention.

Toll-like receptor agonists

Toll-like receptors are pattern recognition receptors that detect microbial pathogen-associated molecular patterns (PAMPs). TLR stimulation, such as TLR9 stimulation, not only can provide a broad range of innate immune stimulation, but can also specifically address the primary driver of immunosuppression in the liver and pancreas. TLR1-10 is expressed in humans and recognizes a number of different microbial PAMPs. In this regard, TLR9 can be responsive to unmethylated CpG-DNA, including microbial DNA. CpG refers to the motif of cytosine and guanine dinucleotides linked by a phosphate backbone. TLR9 is constitutively expressed in B cells, plasmacytoid dendritic cells (pdcs), activated neutrophils, monocytes/macrophages, T cells and MDSCs. TLR9 is also expressed in non-immune cells, including keratinocytes and intestinal, cervical and respiratory epithelial cells. TLR9 can bind its agonist in intracellular compartments within the endosome. Signaling can be performed by MyD88/IkB/NfKB to induce pro-inflammatory cytokine gene expression. Type 1 interferons (e.g., IFN- α, IFN- γ, etc.) that stimulate an adaptive immune response are induced by the parallel signaling pathway of IRF 7. In addition, TLR9 agonists can induce cytokine and IFN production and functional maturation of antigen presenting dendritic cells.

According to one embodiment, TLR9 stimulation may reduce and reprogram MDSCs. MDSCs are key drivers of immunosuppression in the liver. MDSCs also drive the expansion of other suppressor cell types, such as tregs, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). MDSCs can shut down immune cells and immunotherapeutic agents. Furthermore, high MDSC levels are often predictive of poor prognosis for cancer patients. In this regard, the elimination of MDSCs is believed to increase the ability of the host immune system to attack cancer and the ability of immunotherapy to induce a deep response. In one embodiment, TLR9 can convert MDSCs to immunostimulatory M1 macrophages, convert immature dendritic cells to mature dendritic cells, and expand effector T cells, creating a responsive tumor microenvironment that can promote anti-tumor activity.

According to one embodiment, synthetic CpG-oligonucleotides (CPG-ON) that mimic the immunostimulatory properties of microbial CpG-DNA may be developed for therapeutic use. According to one embodiment, the oligonucleotide is an Oligodeoxynucleotide (ODN). There are many different classes of CpG-ODNs, such as class A, class B, class C, class P and class S, which share certain structural and functional features. In this regard, class a CPG-ODNs (or CPG-AODN) are associated with pDC maturation, have little effect on B cells, and have the highest IFNa induction; class B CPG-ODN (or CPG-B ODN) strongly induces B cell proliferation, activates pDC and monocyte maturation, NK cell activation and inflammatory cytokine production; and class C CPG-ODN (or CPG-C ODN) can induce B cell proliferation and IFN-alpha production. Furthermore, according to one embodiment, CPG-C ODN may be associated with the following attributes: (i) unmethylated dinucleotide CpG motifs, (ii) CpG motifs juxtaposed to flanking nucleotides (e.g., AACGTTCGAA), (iii) complete Phosphorothioate (PS) backbones linking nucleotides (as opposed to the natural Phosphodiester (PO) backbones found in bacterial DNA), and (iv) self-complementary palindromic sequences (e.g., AACGTT). In this regard, CPG-C ODNs may bind themselves due to their palindromic nature, thereby creating a double-stranded duplex or hairpin structure.

Furthermore, according to one embodiment, the CPG-C ODN may comprise one or more 5' -TCG trinucleotides, wherein the 5' -T is located at 0, 1, 2 or 3 bases from the 5' -end of the oligonucleotide, and at least one palindromic sequence of at least 8 bases in length comprising one or more unmethylated CG dinucleotides. The one or more 5' -TCG trinucleotide sequences may be spaced 0, 1 or 2 bases from the 5' -end of the palindromic sequence, or the palindromic sequence may contain all or part of the one or more 5' -TCG trinucleotide sequences. In one embodiment, the CpG-C ODN is 12 to 100 bases in length, preferably 12 to 50 bases in length, preferably 12 to 40 bases in length, or preferably 12 to 30 bases in length. In one embodiment, the CpG-C ODN is 30 bases in length. In one embodiment, the ODN is at least (lower limit) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 50, 60, 70, 80, or 90 bases in length. In one embodiment, the ODN is up to (upper limit) 100, 90, 80, 70, 60, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 bases in length.

In one embodiment, the at least one palindromic sequence is 8 to 97 bases in length, preferably 8 to 50 bases in length, or preferably 8 to 32 bases in length. In one embodiment, the at least one palindromic sequence is at least (lower limit) 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 or 30 bases in length. In one embodiment, the at least one palindromic sequence is at most (upper limit) 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12 or 10 bases in length.

In one embodiment, the CpG-C ODN may comprise a sequence of SEQ ID NO: 1.

According to one embodiment, the CpG-C ODN may comprise SD-101.SD-101 is a 30 mer phosphorothioate oligodeoxynucleotide having the following sequence:

5′-TCG AAC GTT CGAACG TTC GAA CGT TCG AAT-3′(SEQ ID NO：1)

the SD-101 bulk drug is separated in the form of sodium salt. The structure of SD-101 is shown in FIG. 1.SD-101 free acid with molecular formula of C ₂₉₃ H ₃₆₉ N ₁₁₂ O ₁₄₉ P ₂₉ S ₂₉ And the molecular weight of the SD-101 free acid is 9.672 daltons. SD-101 sodium salt with molecular formula of C ₂₉₃ H ₃₄₀ N ₁₁₂ O ₁₄₉ P ₂₉ S ₂₉ Na ₂₉ And the molecular weight of the SD-101 sodium salt was 10,309 daltons.

Furthermore, according to one embodiment, the CPG-C ODN sequence may correspond to SEQ ID NO 172 as described in U.S. Pat. No. 9,422,564, which is incorporated herein by reference in its entirety.

In one embodiment, the CpG-C ODN may comprise a sequence having at least 75% homology to any of the foregoing sequences (e.g., SEQ ID NO: 1).

According to another embodiment, the CPG-C ODN sequence may correspond to any of the other sequences described in U.S. Pat. No. 9,422,564. Furthermore, the CPG-C ODN sequence may also correspond to any of the sequences described in U.S. Pat. No. 8,372,413, which is also incorporated herein by reference in its entirety.

According to one embodiment, any CPG-C ODN discussed herein may exist in the form of a pharmaceutically acceptable salt thereof. Exemplary basic salts include ammonium salts, alkali metal salts (e.g., sodium, lithium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts, zinc salts), salts with organic bases (e.g., organic amines) (e.g., N-Me-D-glucosamine, N- [1- (2, 3-dioleoyloxy) propyl ] -N, N, N-trimethylammonium chloride, choline, tromethamine, dicyclohexylamine, t-butylamine, and salts with amino acids (e.g., arginine, lysine, and the like). In one embodiment, the CpG-C ODN is in the form of an ammonium, sodium, lithium, or potassium salt. In a preferred embodiment, the CpG-C ODN is in the sodium salt form. The CpG-C ODN may be provided in a pharmaceutical solution comprising a pharmaceutically acceptable excipient. Alternatively, the CpG-C ODN may be provided as a lyophilized solid which is subsequently reconstituted in sterile water, saline or a pharmaceutically acceptable buffer prior to administration. Pharmaceutically acceptable excipients of the present disclosure include, for example, solvents, fillers, buffers, tonicity adjusting agents and preservatives. In one embodiment, the pharmaceutical composition may comprise excipients that act as one or more of solvents, fillers, buffers, and tonicity adjusting agents (e.g., sodium chloride in saline may act as both an aqueous vehicle and tonicity adjusting agent). The pharmaceutical compositions of the present disclosure are suitable for parenteral and/or transdermal administration.

In one embodiment, the pharmaceutical composition comprises an aqueous vehicle as a solvent. Suitable vehicles include, for example, sterile water, saline solutions, phosphate buffered saline, and ringer's solution. In one embodiment, the composition is isotonic.

The pharmaceutical composition may comprise a filler. Bulking agents are particularly useful when the pharmaceutical composition is lyophilized prior to administration. In one embodiment, the filler is a protective agent that helps stabilize and prevent degradation of the active agent during freezing or spray drying and/or during storage. Suitable fillers are sugars (mono-, di-and polysaccharides) such as sucrose, lactose, trehalose, mannitol, sorbitol, glucose and raffinose.

The pharmaceutical composition may comprise a buffer. The buffer controls the pH to inhibit degradation of the active agent during processing, storage, and optional reconstitution. Suitable buffers include, for example, salts comprising acetate, citrate, phosphate or sulfate. Other suitable buffers include, for example, amino acids such as arginine, glycine, histidine, and lysine. The buffer may further comprise hydrochloric acid or sodium hydroxide. In some embodiments, the buffer maintains the pH of the composition in the range of 4 to 9. In one embodiment, the pH is greater than (lower limit) 4, 5, 6, 7 or 8. In some embodiments, the pH is less than (upper limit) 9, 8, 7, 6, or 5. That is, the pH is in the range of about 4 to 9, with the lower limit being less than the upper limit.

The pharmaceutical composition may comprise a tonicity modifier. Suitable tonicity adjusting agents include, for example, dextrose, glycerin, sodium chloride, glycerin and mannitol.

The pharmaceutical composition may comprise a preservative. Suitable preservatives include, for example, antioxidants and antimicrobials. However, in one embodiment, the pharmaceutical composition is prepared under sterile conditions and in a disposable container, and therefore does not need to include a preservative.

Table 1 describes the batch formulation for 16g/L of SD-101 drug product:

TABLE 1

¹ Based on the amount of the measured content in the solution (excluding the moisture present in the lyophilized powder)

* The SD-101 drug substance contains the sum of all oligonucleotide contents including SD-101

In some embodiments, the unit dose strength may comprise about 0.1mg/mL to about 20mg/mL. In one embodiment, the unit dose strength of SD-101 is 13.4mg/mL.

CpG-C ODNs may contain modifications. Suitable modifications may include, but are not limited to, modifications of 3'oh or 5' oh groups, modifications of nucleotide bases, modifications of sugar components, and modifications of phosphate groups. Modified bases can be included in the palindromic sequence as long as the modified bases retain the same specificity for their natural complement by Watson-Crick base pairing (e.g., the palindromic portion of the CpG-C ODN remains self-complementary).

CpG-C ODNs may be linear, may be circular or include circular portions and/or hairpin loops. CpG-C ODNs may be single-stranded or double-stranded. CpG-C ODN can be DNA, RNA or DNA/RNA hybrids.

CpG-C ODNs may contain naturally occurring or modified non-naturally occurring bases and may contain modified sugars, phosphates, and/or termini. For example, in addition to phosphodiester linkages, phosphate modifications include, but are not limited to, methylphosphonate, phosphorothioate, phosphoramidate (bridged or unbridged), phosphotriester, and phosphorodithioate, and may be used in any combination. In one embodiment, the CpG-C ODN has only phosphorothioate linkages, only phosphodiester linkages, or a combination of phosphodiester linkages and phosphorothioate linkages.

Sugar modifications known in the art, such as 2 '-alkoxy-RNA analogs, 2' -amino-RNA analogs, 2 '-fluoro-DNA and 2' -alkoxy-or amino-RNA/DNA chimeras, as well as other sugar modifications described herein, can also be prepared and combined with any phosphate modification. Examples of base modifications include, but are not limited to, addition of electron withdrawing moieties to C-5 and/or C-6 (e.g., 5-bromocytosine, 5-chlorocytosine, 5-fluorocytosine, 5-iodocytosine) of cytosine of CpG-C ODN and C-5 and/or C-6 (e.g., 5-bromouracil, 5-chlorouracil, 5-fluorouracil, 5-iodouracil) of uracil of CpG-C ODN. As described above, the use of base modifications in the palindromic sequence of a CpG-C ODN should not interfere with the self-complementarity of the bases involved in Watson-Crick base pairing. However, outside the palindromic sequence, modified bases may be used without such limitation. For example, 2' -O-methyl-uridine and 2' -O-methyl-cytidine can be used outside of the palindromic sequence, while 5-bromo-2 ' -deoxycytidine can be used inside and outside of the palindromic sequence. Other modified nucleotides that may be used both internally and externally to the palindromic sequence include 7-deaza-8-aza-dG, 2-amino-dA and 2-thio-dT.

Most ODNs are typically in dynamic equilibrium in duplex (i.e., double-stranded) and hairpin forms, which are generally favored at low oligonucleotide concentrations and higher temperatures. Covalent inter-or intra-strand crosslinking increases the stability of the duplex or hairpin, respectively, to heat, ion, pH and concentration induced conformational changes. Chemical cross-linking can be used to lock polynucleotides into duplex or hairpin forms for physicochemical and biological characterization. Crosslinked ODNs that are conformationally uniform and "locked" in their most active form (duplex or hairpin form) may be more active than their uncrosslinked counterparts. Thus, some CpG-C ODNs of the present disclosure may contain covalent inter-and/or intra-chain crosslinks.

Techniques for preparing polynucleotides and modified polynucleotides are known in the art. Naturally occurring DNA or RNA containing phosphodiester linkages can generally be synthesized by sequentially coupling the appropriate nucleoside phosphoramidite to the 5 '-hydroxyl group of a growing ODN attached at the 3' -terminus to a solid support, followed by oxidation of the intermediate phosphotriester to the phosphotriester. Using this method, once the desired polynucleotide sequence is synthesized, the polynucleotide is removed from the support, the phosphotriester groups are deprotected to phosphodiester, and the nucleobases are deprotected using ammonia or other base.

CpG-C ODNs may contain phosphate-modified oligonucleotides, some of which are known to stabilize ODNs. Thus, some embodiments include a stable CpG-C ODN. The phosphorus derivative (or modified phosphate group) that may be attached to the sugar or sugar analog moiety in the ODN may be a monophosphate, diphosphate, triphosphate, alkylphosphonate, phosphorothioate, phosphorodithioate, phosphoramidate, or the like.

CpG-C ODNs can comprise one or more ribonucleotides (containing ribose as the sole or major sugar component), deoxyribonucleotides (containing deoxyribose as the major sugar component), modified sugars or sugar analogs. Thus, in addition to ribose and deoxyribose, the sugar moiety may be pentose, deoxypentose, hexose, deoxyhexose, glucose, arabinose, xylose, lyxose, and saccharide analog cyclopentyl. The sugar may be in the form of a pyranosyl or furanosyl group. In CpG-C oligonucleotides, the sugar moiety is preferably a ribofuranoside of ribose, deoxyribose, arabinose or 2' -0-alkylribose, and the sugar may be attached to the corresponding heterocyclic base in an anomeric configuration. The preparation of these sugars or sugar analogues and the corresponding nucleosides in which these sugars or analogues are attached to heterocyclic bases (nucleobases) is known per se and therefore need not be described herein. Sugar modifications can also be made in the preparation of CpG-C ODNs and combined with any phosphate modifications.

The heterocyclic bases or nucleobases incorporated into the CpG-C ODN can be naturally occurring major purine and pyrimidine bases (i.e., uracil, thymine, cytosine, adenine and guanine, as described above), as well as naturally occurring and synthetic modifications of the major bases. Thus, the CpG-C ODN may include one or more of inosine, 2 '-deoxyuridine, and 2-amino-2' -deoxyadenosine.

According to another embodiment, the CPG-ODN is one of a class A CPG-ODN (CPGP-A ODN), a class B CPG-ODN (CPG-B ODN), a class P CPG-ODN (CPG-P ODN) and a class S CPG-ODN (CPG-S ODN). Ext> inext> thisext> regardext>,ext> CPGext> -ext> Aext> ODNext> mayext> beext> CMPext> -ext> 001ext>.ext>

In another embodiment, the CPG-ODN may be Tilsotolimod (IMO-2125).

Checkpoint inhibitors

According to one embodiment, the checkpoint inhibitor may comprise a programmed death 1 receptor (PD-1) antagonist. The PD-1 antagonist may be any compound or biological molecule that blocks the binding of programmed cell death 1 ligand 1 (PD-L1) expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells), and preferably also blocks the binding of PD-L2 programmed cell death 1 ligand 2 (PD-L2) expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCDlL1, PDL1, B7H1, B7-4, CD274 and B7-H of PD-L1; and PDCD1L2, PDL2, B7-DC, btdc, and CD273 for PD-L2. In any of the therapeutic methods, medicaments and uses of the invention for treating a human subject, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, preferably blocks the binding of human PD-L1 and PD-L2 to human PD-1.

According to one embodiment, the PD-1 antagonist may comprise a monoclonal antibody (mAb) or antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, humanized antibody, or chimeric antibody, and may include human constant regions. In some embodiments, the human constant region is selected from the group consisting of IgG1, igG2, igG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, fab '-SH, F (ab') ₂ scFv and Fv fragments.

According to one embodiment, the PD-1 antagonist may comprise an immunoadhesin which specifically binds to PD-1 or PD-L1, preferably to human PD-1 or human PD-L1, e.g. a fusion protein comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region of an immunoglobulin molecule.

According to one embodiment, the PD-1 antagonist may inhibit the binding of PD-L1 to PD-1, preferably also PD-L2 to PD-1. In some embodiments of the above methods of treatment, medicaments and uses, the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1 and blocks the binding of PD-L1 to PD-1. In one embodiment, the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain.

According to one embodiment, the PD-1 antagonist may be one of nivolumab (nivolumab), pembrolizumab (pembrolizumab), and cemipramiab (cemiplimab).

According to another embodiment, pembrolizumab is administered intravenously (Iv) via the peripheral vein at a dose of 200mg every three weeks ("Q3W"). In yet another embodiment, pembrolizumab is concomitantly administered with SD-101 at the same time, about the same time, or on the same day. In another embodiment, pembrolizumab is administered weekly, every other week, every third week, every fourth week, or monthly after one or more cycles of SD-101. In another embodiment, pembrolizumab is administered for a period of up to six months.

According to another embodiment, nivolumab is administered intravenously (Iv) via the peripheral vein at a dose of 240mg every two weeks ("Q2W"). In yet another embodiment, the nivolumab is administered concomitantly with, at about the same time as, or on the same day as SD-101. In another embodiment, after one or more cycles of SD-101 administration, nivolumab is administered weekly, every other week, every third week, every fourth week, or monthly.

According to another embodiment, the checkpoint inhibitor may comprise a PD-L1 antagonist. In this regard, the PD-L1 antagonist may be one of atilizumab (atezolizumab), avistuzumab (avelumab), and devaluzumab (durvalumab).

According to another embodiment, the CPI may comprise a CTLA-4 antagonist. In this aspect, the CTLA-4 antagonist can be ipilimumab (ipilimumab). According to another embodiment, ipilimumab is administered Intravenously (IV) via the peripheral vein at a dose of 3mg/kg every three weeks. In yet another embodiment, ipilimumab is concomitantly administered with SD-101 at the same time, about the same time, or on the same day. In another embodiment, after one or more cycles of SD-101 administration, nivolumab is administered weekly, every other week, every third week, every fourth week, or monthly.

Device for realizing local area delivery

According to one embodiment, any of the above devices may comprise any device for achieving delivery to a localized area of a tumor, including the catheter itself, or may comprise the catheter along with other components that may be used in combination with the catheter (e.g., filter valve, balloon, pressure sensor system, pump system, syringe, external delivery catheter, etc.). In certain embodiments, the catheter is a microcatheter.

In some embodiments, the device may have one or more attributes including, but not limited to, self-centering capability capable of providing even distribution of therapy in a downstream branching network of blood vessels; an anti-reflux capability (e.g., using valves and filters, and/or a balloon) capable of blocking or inhibiting retrograde flow of TLR agonists; a system for measuring intravascular pressure; and means for regulating the pressure within the blood vessel. In retrograde intravenous infusion, the pressure in the blood vessel increases after deployment of the device, thereby preventing retrograde flow. Infusion further increases vascular pressure in proportion to the infusion rate. In arterial infusion, deployment of the device reduces vascular pressure and flow. Infusion then increases the vascular pressure in proportion to the infusion rate. In some embodiments, the system is designed to monitor real-time pressure continuously throughout the process.

In some embodiments, devices that may be used to perform the methods of the present invention are devices as disclosed in U.S. patent No. 8,500,775, U.S. patent No. 8,696,698, U.S. patent No. 8,696,699, U.S. patent No. 9,539,081, U.S. patent No. 9,808,332, U.S. patent No. 9,770,319, U.S. patent No. 9,968,740, U.S. patent No. 10,813,739, U.S. patent No. 10,588,636, U.S. patent No. 11,090,460, U.S. patent publication No. 2018/0193591, U.S. patent publication No. 2018/0250469, U.S. patent publication No. 2019/0298983, U.S. patent publication No. 2020/0038586, and U.S. patent publication No. 2020-0383688, the entire contents of which are incorporated herein by reference.

In some embodiments, the device is the device disclosed in U.S. patent No. 9,770,319. In certain embodiments, the device may be a device known as a Surefire infusion system.

In some embodiments, the device supports measurement of intravascular pressure during use. In some embodiments, the device is the device disclosed in U.S. patent application Ser. No. 16/431,547. In certain embodiments, the device may be a device known as a trislus infusion system (sometimes also referred to as a SEAL device). In some embodiments, the device may be what is referred to as

A device for infusing a system. In some embodiments, the device may be a device known as a SEAL device. In certain embodiments, the catheter device may be described as an anti-reflux microcatheter (TIS-21120-60) manufactured by TriSalus life sciences (TriSalus Life Sciences). In some embodiments, the device may be a temporary blocking device, such as a SEAL device.

In some embodiments, the SEAL device may be a dual catheter mechanically actuated infusion system equipped with a structure at the distal end of the device for reversibly occluding blood flow during retrograde intravenous infusion (RVI) procedures. According to one embodiment, the structure at the distal end of the device may be a braided filament structure having a fluid impermeable membrane disposed on a proximal portion of the braided structure and a fluid permeable coating (or covering) on a distal portion of the braided structure. The geometry of the device may further allow for direct continuous measurement of the pressure of the vasculature distal to the infusion lumen of the device during therapy delivery. In RVI procedures, deployment of the device and infusion of therapeutic agents may modulate distal vascular pressure.

In some embodiments, the TLR agonist can be administered via PEDD by a device. In some embodiments, TLR agonists may be administered while monitoring pressure in the blood vessel, which may be used to adjust and correct the positioning of the device at the infusion site and/or to adjust the infusion rate. The pressure may be monitored by, for example, a pressure sensor system comprising one or more pressure sensors.

Infusion rates can be adjusted to alter vascular pressure, which can facilitate penetration of TLR agonists into target tissues or tumors. In some embodiments, a syringe pump may be used as part of the delivery system to regulate and/or control the infusion rate. In some embodiments, a pump system may be used to regulate and/or control the infusion rate. In some embodiments, the infusion rate may be about 0.1 cc/min to about 40 cc/min, or about 0.1 cc/min to about 30 cc/min, or about 0.5 cc/min to about 25 cc/min, or about 0.5 cc/min to about 20 cc/min, or about 1 cc/min to about 15 cc/min, or about 1 cc/min to about 10 cc/min, or about 1 cc/min to about 8 cc/min, or about 1 cc/min to about 5 cc/min.

The invention will be further illustrated and/or shown in the following examples, which are given for illustration/display purposes only and are not intended to limit the invention in any way.

Methods comprising administration to the pancreas

In one embodiment, the methods of the invention comprise a method of treating pancreatic cancer, the method comprising administering a toll-like receptor agonist to a patient in need thereof, wherein the toll-like receptor agonist is administered to a solid tumor in the pancreas by means of a device in the manner of PRVI. PRVI refers to infusion of treatment of solid tumors in the pancreas through one or more branches of the pancreatic venous drainage system. According to one embodiment, the toll-like receptor agonist is introduced by introducing a device, such as a catheter and/or a device that facilitates pressure-enabled delivery, percutaneously and hepatially into a branch of the pancreatic venous drainage system. According to one embodiment, the toll-like receptor agonist is a TLR9 agonist, and in some embodiments, the TLR9 agonist is SD-101. In one embodiment, the patient is a human patient.

In one embodiment, delivery of treatment by PRVI may be a more efficient way to provide TLR9 agonists to pancreatic tumors. In particular, in contrast to systemic intravenous and local area intra-arterial therapies, PRVI can be used to provide treatment of tumors independent of arterial supply to the tumor, and thus can be a more effective means of delivering TLR9 agonists and treating pancreatic cancer. For example, for PRVI, TLR9 agonists can be delivered to tumors via a sub-selective catheter guidance method that utilizes a drainage vein targeting pancreatic tumors. For example, a TLR9 agonist may be delivered to a tumor in one or more branches of the pancreatic venous drainage system. In this regard, digital subtraction angiography with Computed Tomography (CT) may be used to catheterize veins draining pancreatic tumors with a delivery device (e.g., a catheter and/or a device that facilitates pressure-enabled delivery) in order to deliver TLR9 agonists in a retrograde fashion.

In one embodiment, the methods of the invention include a method of treating pancreatic cancer, the method comprising administering a toll-like receptor agonist to a patient in need thereof, wherein the toll-like receptor agonist is administered by device infusion through the pancreatic arterial system to a solid tumor in the pancreas. According to one embodiment, the toll-like receptor agonist is introduced by percutaneous introduction of a device, such as a catheter and/or a device that facilitates pressure-enabled delivery, into the pancreatic arterial system. For example, the pancreatic arterial system may be accessed through the spleen artery, the gastroduodenal artery, or the subduodenal artery. In this regard, the head may enter the anterior and posterior pancreas-duodenal arteries through the gastroduodenal arteries, while the body and tail may enter the dorsal, large or tail pancreas arteries from the spleen arteries. Smaller blood supply vessels may be selected from these vessels as needed to treat the target tissue. According to one embodiment, the toll-like receptor agonist is a TLR9 agonist, and in some embodiments, the TLR9 agonist is SD-101. In one embodiment, the patient is a human patient.

Pancreatic cancer may include solid tumors in the pancreas, such as exocrine tumors, such as pancreatic cancer, or endocrine tumors, such as neuroendocrine cancer. Examples include, but are not limited to, ductal adenocarcinomas (including pancreatic ductal adenocarcinomas and locally advanced pancreatic ductal adenocarcinomas) and acinar adenocarcinomas. In one embodiment, the tumor is unresectable or resected unreasonably due to the presence of advanced disease. Furthermore, in one embodiment, the tumor is metastatic pancreatic cancer.

According to one embodiment, the method of the invention comprises a method for treating pancreatic cancer, wherein the subject is eighteen years old or older and exhibits histologically or cytologically confirmed evaluable or measurable locally advanced unresectable PDAC according to recistv1.1 standard. In another embodiment, a focused imaging validation of the unresectable disease defined by the NCCN occurs. In another embodiment, the methods of the invention may comprise administering to a subject exhibiting an eastern tumor cooperative group ("ECOG") performance score ("PS") of 0 to 1. In another embodiment, the method of the invention may comprise administering to a subject exhibiting a suitable venous anatomy on a CT iv-gram, the suitable venous anatomy being defined as the absence of a total occlusion of the portal vein, the splenic vein, or the superior mesenteric vein.

According to another embodiment, the method of the invention comprises a method for treating pancreatic cancer, wherein the subject has received standard of care chemo-or systemic chemo-regimen without complete radiographic response. Examples of standard-of-care chemotherapies include gemcitabine) +albumin-bound paclitaxel or FOLFIRINOX. In addition, radiation with or without chemotherapy is also acceptable as a standard of care regimen. In another embodiment, the subject has not received prior cytotoxic chemotherapy, targeted therapy, or external radiation therapy within 14 days prior to screening.

According to another embodiment, the method of the invention comprises a method for treating pancreatic cancer, wherein the subject has sufficient hematologic and organ function. In another embodiment, the subject has no past history of malignancy or other concurrent malignancy unless the malignancy is clinically insignificant, no ongoing treatment is required, and the subject is clinically stable. In another embodiment, the subject has a disease measurable in the liver according to recistv.1.1 criteria.

According to another embodiment, the method of the invention comprises a method for treating pancreatic cancer, wherein the subject has an expected lifetime of greater than 3 months according to the estimate of the researcher. According to yet another embodiment, the subject has a QTc interval of 480msec or less.

In another embodiment, all associated clinically significant drug-related toxicities from previous cancer therapies are alleviated prior to treatment. In this example, relief is +.1 or the pre-treatment level of the patient. In further embodiments, the subject may have grade 2 alopecia and endocrinopathy controlled by replacement therapy.

In another embodiment, the methods of the invention can include administering to a subject having sufficient organ function at the time of screening. In one embodiment, a subject with sufficient organ function may exhibit one or more of the following: (i) Platelet count > 100,000/. Mu.L, (2) hemoglobin ≡8.0g/dL, (3) white blood cell count (WBC) +.2,000/. Mu.L (4) serum creatinine +.2.0 mg/dL unless measured creatinine clearance > 30 ml/min calculated by the Cockcroft-Gao Erte equation (Cockcroft-Gault formula), (5) total bilirubin and direct bilirubin +.2.0×upper normal limit (ULN) and alkaline phosphatase +.5×ULN, (6) total bilirubin up to 3.0mg/dL for patients with recorded Gilbert disease, (7) ALT and AST +.5×ULN, and (8) amylase and lipase +.3×ULN, and (8) prothrombin time/International Normalized Ratio (INR) or activated partial thromboplastin time (aPTT) detection result +.1.5×ULN (applicable only to patients not receiving anticoagulation treatment; stable dose at least 4 weeks before the first week of study).

According to another embodiment, the tumor is unresectable.

According to another embodiment, the methods of the invention may be administered with other cancer therapeutic agents (e.g., immunomodulators, tumor killing agents, and/or other targeted therapeutic agents).

According to one embodiment, TLR9 therapy can achieve cell therapy by modulating the immune system.

In one embodiment, the above method of administering to the pancreas results in penetration of the toll-like receptor agonist through the entire solid tumor, through the entire tumor, or through substantially the entire tumor. In one embodiment, these methods enhance perfusion of toll-like receptor agonists to patients in need thereof, including by overcoming interstitial fluid pressure and solid stress. In one embodiment, these methods are capable of delivering toll-like receptors to tumor areas that are not reachable by the systemic circulation. In another embodiment, these methods deliver a higher concentration of toll-like receptor agonist into such tumors and less toll-like receptor agonist into non-target tissue than other therapies (such as conventional systemic delivery via peripheral veins or via direct intratumoral injection). In one embodiment, these methods result in a reduction or elimination of the size, growth rate, or solid tumor.

In some embodiments, the dose of TLR9 agonist (e.g., SD-101) can be about 0.01mg, about 0.03mg, about 0.05mg, about 0.1mg, about 0.3mg, about 0.5mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, and about 12mg. In some embodiments, SD-101 is administered at doses of 16mg and 20 mg. Administration of milligram amounts of SD-101 (e.g., about 2 mg) describes administration of about 2mg of the composition shown in FIG. 1. For example, such amounts of SD-101 (e.g., an amount of about 2 mg) may also be present in compositions containing materials other than such amounts of SD-101, such as other related and unrelated compounds. Equivalent molar amounts of other pharmaceutically acceptable salts are also contemplated.

In some embodiments, the dose of TLR9 agonist (e.g., SD-101) may be between about 0.01mg and about 12mg, between about 0.01mg and 10mg, between about 0.01mg and about 8mg, and between about 0.01mg and 4 mg. In some embodiments, the dose of TLR9 agonist (e.g., SD-101) may be between about 2mg to about 12mg, between 2mg to about 10mg, between about 2mg to about 8mg, and between about 2mg to 4 mg. In some embodiments, the dose of TLR9 agonist (e.g., SD-101) may be less than about 12mg, less than about 10mg, less than about 8mg, less than about 4mg, or less than about 2mg. Such doses may be administered daily, weekly or every other week. In one embodiment, the dose of SD-101 is increased incrementally, for example by administering about 0.5mg, then about 2mg, then about 4mg, then about 8mg, then about 12mg.

In some embodiments, the methods of the invention can comprise administering a dosing regimen comprising cycles, wherein one or more cycles comprise administering SD-101 via PRVI and PEDD. As used herein, a "cycle" is a repetition of a sequence of administration. In one embodiment, one cycle contains one dose per cycle. In one embodiment, a treatment cycle according to the present invention may comprise an SD-101 dosing period followed by a "withdrawal" period or rest period. In another embodiment, the cycle further comprises one week, two weeks, three weeks, four weeks, or twenty-eight days as a rest period after weekly administration of SD-101 in addition to the single dose per cycle. In another embodiment, the dosing regimen comprises at least one, at least two, or at least three cycles or more. In another embodiment, the treatment comprises administration during two cycles, one dose per cycle, each cycle being separated by a month.

In some embodiments, the invention relates to the use of a TLR9 agonist in the manufacture of a medicament for treating a solid tumor in the pancreas (e.g., locally advanced pancreatic ductal adenocarcinoma), the method comprising administering the TLR9 agonist to a patient in need thereof, wherein the TLR9 agonist is administered to such solid tumor in the pancreas by means of a device in the manner of PRVI.

In some embodiments, SD-101 is administered at a dose of 0.5mg by PRVI for the treatment of locally advanced pancreatic ductal adenocarcinoma, and in some embodiments, SD-101 is further administered by a means for modulating pressure (i.e., PEDD). In some embodiments, SD-101 is administered at a dose of 0.5mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor, wherein the checkpoint inhibitor is pembrolizumab. In some embodiments, SD-101 is administered at a dose of 0.5mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is nivolumab. In some embodiments, SD-101 is administered at a dose of 0.5mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor, wherein the checkpoint inhibitor is ipilimumab. In some embodiments, SD-101 is administered in combination with pembrolizumab, nivolumab, and ipilimumab at a dose of 0.5mg by PRVI and by a means of modulating pressure.

In some embodiments, SD-101 is administered at a dose of 2mg by PRVI for the treatment of locally advanced pancreatic ductal adenocarcinoma, and in some embodiments, SD-101 is further administered by a means for modulating pressure (i.e., PEDD). In some embodiments, SD-101 is administered at a dose of 2mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is pembrolizumab. In some embodiments, SD-101 is administered at a dose of 2mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is nivolumab. In some embodiments, SD-101 is administered at a dose of 2mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is ipilimumab. In some embodiments, SD-101 is administered in combination with pembrolizumab, nivolumab, and ipilimumab at a dose of 2mg by PRVI and by a means of modulating pressure.

In some embodiments, SD-101 is administered at a dose of 4mg by PRVI for the treatment of locally advanced pancreatic ductal adenocarcinoma, and in some embodiments, SD-101 is further administered by a means for modulating pressure (i.e., PEDD). In some embodiments, SD-101 is administered at a dose of 4mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is pembrolizumab. In some embodiments, SD-101 is administered at a dose of 4mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is nivolumab. In some embodiments, SD-101 is administered at a dose of 4mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is ipilimumab. In some embodiments, SD-101 is administered in combination with pembrolizumab, nivolumab, and ipilimumab at a dose of 4mg by PRVI and by a means of modulating pressure.

In some embodiments, SD-101 is administered at a dose of 8mg by PRVI for the treatment of locally advanced pancreatic ductal adenocarcinoma, and in some embodiments, SD-101 is further administered by a means for modulating pressure (i.e., PEDD). In some embodiments, SD-101 is administered at a dose of 8mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is pembrolizumab. In some embodiments, SD-101 is administered at a dose of 8mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is nivolumab. In some embodiments, SD-101 is administered at a dose of 8mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is ipilimumab. In some embodiments, SD-101 is administered in combination with pembrolizumab, nivolumab, and ipilimumab at a dose of 8mg by PRVI and by a means of modulating pressure.

In some embodiments, SD-101 is administered at a dose of 12mg by PRVI for the treatment of locally advanced pancreatic ductal adenocarcinoma, and in some embodiments, SD-101 is further administered by a means for modulating pressure (i.e., PEDD). In some embodiments, SD-101 is administered at a dose of 12mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is pembrolizumab. In some embodiments, SD-101 is administered at a dose of 12mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is nivolumab. In some embodiments, SD-101 is administered at a dose of 12mg via a device that modulates vascular pressure in combination with a checkpoint inhibitor via PRVI, wherein the checkpoint inhibitor is ipilimumab. In some embodiments, SD-101 is administered in combination with pembrolizumab, nivolumab, and ipilimumab at a dose of 12mg by PRVI and by a means of modulating pressure.

In some embodiments, the methods of the invention comprise the step of allowing the infusion to remain in the affected tissue (e.g., pancreas) for a different amount of time. For example, the process of the present invention comprises a residence time of about zero to about twenty minutes. In another embodiment, the process of the present invention comprises a residence time of about five to about ten minutes.

In some embodiments, the methods of the invention result in treatment of a target lesion. In this example, the method of the invention may result in a complete response, including the disappearance of all target lesions. In some embodiments, the methods of the invention may result in a partial response comprising a reduction of at least 30% in the sum of the longest diameters of the target lesions, referenced to the sum of the baseline longest diameters. In some embodiments, the methods of the invention may result in stable target lesions that include conditions that neither shrink sufficiently to meet partial responses nor increase sufficiently to meet progressive disease, with reference to the smallest longest diameter since initiation of treatment. In such an embodiment, the progressive disease is characterized by an increase in the sum of the longest diameters of the target lesions of at least 20%, referenced to the sum of the smallest longest diameters recorded since the onset of the lesion or the appearance of 1 or more new lesions. The sum must show an absolute increase over 5 mm.

In another embodiment, the methods of the invention result in the treatment of non-target lesions. In this example, the method of the invention may result in a complete response, including the disappearance of all non-target lesions. In some embodiments, the methods of the invention result in the persistent presence of one or more non-target lesions. In such embodiments, the progressive disease is characterized by the definite progression of the non-target lesions present, and/or the appearance of one or more new lesions.

In some embodiments, the methods of the invention result in beneficial overall response rates, such as the overall response rate according to recistv.1.1. In those embodiments, the overall response resulting from the methods of the invention is a complete response, wherein the subject exhibits a complete response to the target lesion, a complete response to the non-target lesion, and no new lesions. In other embodiments, the overall response resulting from the methods of the invention is a partial response, wherein the subject exhibits a complete response to a target lesion, a non-complete response to a non-target lesion, and a non-progressive disease, and is free of new lesions. In other embodiments, the overall response resulting from the methods of the invention is a partial response, wherein the subject exhibits a partial response to the target lesion, a non-progressive disease to a non-target lesion, and no new lesions. In another embodiment, the overall response resulting from the methods of the invention is a stable disease, wherein the subject exhibits stable target lesions, non-progressive disease other than target lesions, and no new lesions.

In some embodiments, the methods of the invention result in an increase in the duration of the overall response. In some embodiments, the duration of the overall response is measured from the time the complete response or partial response (based on the first recorded) meets the measurement criteria until the first day of recurrent or progressive disease is objectively recorded (the minimum measurement recorded since the initiation of the treatment is taken as a reference for progressive disease). The duration of the overall complete response may be measured from the time the measurement criteria for the complete response is first met until the first day of progressive disease is objectively recorded. In some embodiments, the duration of stable disease is measured from the beginning of treatment until the progress criteria are met, with the minimum measurement recorded since the beginning of treatment (including baseline measurement) as a reference.

In other embodiments, the methods of the invention result in improved overall survival. For example, the total survival rate may be calculated from the date of registration to the time of death. Patients who either survived until the end of the study or were withdrawn before the end of the study will be examined on the day they were last known to survive.

In other embodiments, the methods of the invention result in progression free survival. Progression-free survival may be calculated, for example, starting from the date of recurrence (or other well-defined indicator of disease progression) or the date of death (based on the first occurrence). Patients who did not record recurrence and remained alive before the end of the study or who were withdrawn before the end of the study will be reviewed on the date of the last radiological evidence recording no recurrence.

In some embodiments, the methods of the invention result in beneficial overall response rates, such as overall response rates according to iRECIST. In another embodiment, the method results in a clinical benefit (e.g., complete response + partial response + stable disease). In another embodiment, the method of the invention results in an improvement in eastern cooperative oncology group physical force status (ECOG PS) over time as compared to baseline. In yet another embodiment, the methods of the present invention result in improved quality of life using the European cancer research and tissue cancer quality of life questionnaire for treatment (EORTC-QLQ-C30) tool.

According to another embodiment, the method of the invention comprises a method for treating locally advanced pancreatic ductal adenocarcinoma, wherein the administration of SD-101 results in a reduction of tumor burden. In some embodiments, the tumor burden is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

According to another embodiment, the method of the invention comprises a method for treating locally advanced pancreatic ductal adenocarcinoma, wherein the administration of SD-101 results in a reduction of tumor progression. In some embodiments, tumor progression is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

According to another embodiment, the methods of the invention comprise a method for treating locally advanced pancreatic ductal adenocarcinoma, wherein administration of SD-101 reprograms hepatic MDSC compartments to enable immune control of liver metastasis and/or improve response to systemic anti-PD-1 therapy by elimination of MDSCs. In some embodiments, the methods of the invention are superior in controlling MDSCs. In some embodiments, the methods of the invention comprise a method for locally advanced pancreatic ductal adenocarcinoma, wherein administration of SD-101 reduces MDSC cells (CD11b+Gr1+), monocytic MDSC (M-MDSC; CD11b+Ly6C+) cells, or granulocytic MDSC (G-MDSC; CD11b+LY6G+) cells. According to another embodiment, the methods of the invention enhance M1 macrophages. According to yet another embodiment, the method of the invention reduces M2 macrophages.

In another embodiment, the methods of the invention increase nfkb phosphorylation. In yet another embodiment, the methods of the invention increase IL-6. In another embodiment, the methods of the invention increase IL10. In yet another embodiment, the methods of the invention increase IL-29. In another embodiment, the method of the invention increases IFN alpha. As another example, the method of the invention reduces STAT3 phosphorylation.

Example 1

In this example, tumor volumes and tumor weights of whole body saline infusion, saline infusion by PRVI/PEDD, whole body SD-101 infusion, and SD-101 infusion by PRVI/PEDD were compared in a murine model. Fig. 2A depicts data for tumor volumes, while fig. 2B depicts a graph illustrating the mean and standard error of the mean (SEM) for tumor volumes. Fig. 3A depicts data of tumor weight, while fig. 3B depicts graphs illustrating mean and SEM of tumor weight.

From the data and corresponding graphs, it can be seen that there is a trend towards improvement.

Example 2

In this example, SD-101 sequence oligonucleotides were synthesized and conjugated to IRDye800CW (ex.767 nm, em.791 nm) fluorophores.

/5IRD800CW/T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T

The labeled SD-101 was then dissolved in saline solution and administered in a pig model via a PEDD device (i.e., SEAL device) at a rate of 2 ml/min. Blood was circulated for 60 minutes, then animals were euthanized and pancreatic tissue was collected. Near infrared imaging was used to quantify signal intensity (a measure of the concentration of labeled SD-101 in tissue) and the tissue distribution treated. Untreated porcine pancreas was used as a reference for normalized signal intensity.

Three different experimental groups were performed:

stay for 0 min, inject 10cc at 2 cc/min with aspiration

Stay for 20 minutes, inject 10cc at 2 cc/min with aspiration

Stay for 0 min, inject 20cc at 2 cc/min, no aspiration

In this analysis, any pigs that showed significant venous perforation and/or fluid extravasation under fluoroscopy were excluded. Five such events are recorded in the data table. Each sample, including treatment group, date of surgery and status of exclusion, was determined in table 2 (pig sample in PRVI study).

TABLE 2

Treatment 1 excluded two cases, treatment 2 excluded one case, and treatment 3 excluded two cases. As a result, 6 samples of treatment 1, 4 samples of treatment 2, and 5 samples of treatment 3 were included in the analysis.

Data analysis was done on near infrared images from these studies using MATLAB and single channel analysis V2 kits. The volume is calculated from the number of pixels. The signal is adjusted to the original dose measured from the syringe.

A summary of the data outputs is shown in table 3 (data output from analysis). It includes pressure measurements obtained from the pressure sensor of Edwardsies life sciences (Edwards Lifesciences) and the Quantent pressure monitor.

TABLE 3 Table 3

All statistics were performed using Minitab.

Analysis of variance

TABLE 4 Table 4

Source	DF	Adj SS	Adj MS	F value	P value
						Treatment of	2	3.240	1.620	0.12	0.889
Error of	12	164.093	13.674
						Totals to	14	167.333

No significant difference was found at p=.889.

Signal comparisons and post-hoc Tukey pairwise comparisons were performed for three treatment groups for one-way ANOVA.

Analysis of variance

Wheat 5

Source	DF	Adj SS	Adj MS	F value	P value
						Treatment of	2	9790602	4895301	0.69	0.521
Error of	12	85331223	7110935
						Totals to	14	95121824

No significant difference was found at p=.521.

The volumes and signals were linearly regressed using the treatment groups as fixed variables and pressures as continuous variables (collapse, expansion and/or peak) to see if the pressure had an effect on the volumes or signals.

Analysis of variance-volume

TABLE 6

Analysis of variance-signal

Wheat 7

Source	DF	Adj SS	Adj MS	F value	P value
						Regression	5	44965015	8993003	1.61	0.251
Collapse_pressure	1	102665	102665	0.02	0.895
						Deployment_pressure	1	520184	520184	0.09	0.767
Peak_pressure	1	21744188	21744188	3.90	0.080
						Treatment of	2	7122449	3561224	0.64	0.550
Error of	9	50156810	5572979
						Totals to	14	95121824

No significant variables were found.

Table 8 summarizes some descriptive statistics.

TABLE 8

A typical human pancreas is generally about 75cc. It is expected that 50kg pigs are similar or may be somewhat smaller. If MATLAB analysis is used and total target and total non-target are added and volume calculated, then total organ volume should be equal. When this was done, the average value of all pigs in this study was 73.62cc. Thus, this method appears to be an accurate method of determining the total volume of the pancreas. Table 9 summarizes the calculated organ volumes.

TABLE 9

Sample of	Organ volume
		P21040	91.68
P21041	161.72
		P21045	63.95
P21046	52.04
		P21062	65.35
P21088	77.89
		P21089	73.86
P21090	72.76
		P21092	32.64
P21093	94.29
		P21112	85.15
P21126	46.93
		P21127	46.03
P21133	64.38
		P21134	75.63

The delivered dose was also quantified by a near infrared camera prior to delivery. This is done by taking an image of the syringe after the dose has been mixed with saline and quantifying the signal. Table 10 summarizes the total doses delivered.

Table 10

Sample of	Dosage of
		P21040	372,333
P21041	372,000
		P21045	343,000
P21046	339,000
		P21062	375,000
P21088	361,333
		P21089	365,667
P21090	363,000
		P21092	378,333
P21093	371,667
		P21112	442,667
P21126	444,000
		P21127	440，667
P21133	399,000
		P21134	341,000

The percent tissue coverage and delivered dose are shown in table 11 below.

TABLE 11

These two calculations indicate that an average of 0.6% of the total marker SD-101 dose is absorbed by tissue that occupies 7.5% of the pancreas volume. While this represents a fraction of the total dose, the local concentration of SD-101 in the target tissue is enriched relative to the concentration that the tissue would normally receive systemic treatment delivery. Thus, using PRVI, lower doses of SD-101 can be used to achieve an intake/response similar to systemic infusion.

Further analysis was performed without excluding any surgery from the dataset, except that P21116 and P21117 did not receive PRVI infusion due to the inability to locate the device after perforation. Data from all queues were collected for analysis (n=18).

It has been determined that PRVI increased local vascular pressure by 14+2mmhg during infusion and local concentration of SD-101 increased 12.6-fold relative to adjacent non-target tissue within the pancreas (17.12±2.39 target tissue versus 1.40±0.05 non-target tissue, p=0.000) (fig. 4, table 12). The tissue targeting of PRVI was found to be highly selective, with an average of 7.66% of the tissue volume exposed to labeled SD-101.

Table 12

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Outlier testing was performed using MiniTab software. The signal data of P21093 (9471 lu) was determined to be an outlier of the dataset. Analysis was re-analyzed, excluding data in P21093.

After removal of outliers, it has been determined that PRVI increased local vascular pressure by 13±2mmHg during infusion, and local concentration of SD-101 increased 11.3-fold relative to adjacent non-target tissue within the pancreas (16.01±1.78 target tissue versus 1.41±0.06 non-target tissue, p=0.000) (fig. 5, table 13). The tissue targeting of PRVI was found to be highly selective, with an average of 7.33% of the tissue volume exposed to labeled SD-101.

TABLE 13

Example 3

In this example, the signal intensity (therapeutic absorption) and treatment volume of PEDD devices and end hole catheters were compared in a pig model using IDR800 CW-labeled SD-101.

In this regard, two different experimental groups are included in the following summary: (i) SEAL device: stay for 0 min, inject 10cc at 2 cc/min with aspiration and (ii) tip hole catheter: stay for 0 min, inject 10cc at 2 cc/min, no aspiration.

Data generated from the SEAL device (residence 0 minutes, 10cc injected at 2 cc/min, with aspiration) is described in table 14.

TABLE 14

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Data generated from a tip hole catheter (residence 0 min, 10cc injected at 2 cc/min without aspiration) is shown in table 15.

TABLE 15

Fig. 6 depicts the treatment volume of the SEAL device compared to the end hole catheter. In this regard, use of the SEAL device resulted in a 6.8-fold increase in the volume of treated tissue.

Fig. 7 depicts the processed signal strength of the SEAL device compared to an end hole catheter. In this regard, use of the SEAL device resulted in a 12-fold increase in the labeled SD-101 delivered to the tissue, as measured by signal intensity.

A similar test was performed as outliers were removed. In this regard, minitab software was used to determine if outliers exist in the SEAL device and end-hole infusion dataset. This analysis determines the presence of outliers in the end hole signal dataset (P21148, 1122.88lu signal intensity). The data was re-analyzed, excluding the data in P21148.

Table 16 describes the end hole catheter data with outliers removed.

Table 16

Fig. 8 depicts the treatment volume of the SEAL device compared to an end hole catheter with outlier data removed. In this regard, use of the SEAL device resulted in a 10.6 fold increase in the volume of treated tissue.

Fig. 9 depicts the processed signal strength of the SEAL device compared to an end hole catheter, with outlier data removed. In this regard, use of the SEAL device resulted in 46-fold increase in the labeled SD-101 delivered to the tissue, as measured by signal intensity.

FIG. 10A depicts the distribution pattern of labeled SD-101 delivered through an end hole catheter, while FIG. 1DB depicts the distribution pattern of labeled SD-101 delivered through a SEAL device. In this regard, infusion using the end hole catheter resulted in deposition of labeled SD-101 along the vein with minimal penetration into the tissue. However, treatment delivery using the SEAL device results in penetration into tissue outside of the primary drainage vein.

Example 4

In this example, it is assumed that pancreatic retrograde intravenous infusion (PRVI) of TLR9 agonist SD-101 using PEDD (e.g., SEAL device) can enhance the response rate of locally advanced PDAC patients to CPI. Furthermore, extrapancreatic lesions may also benefit from enhanced immune responsiveness through the remote effects of SD-101PEDD/PRVI in patients who also receive CPI systemic infusion. Thus, the responsiveness of locally advanced PDACs to immunotherapy can be optimized while achieving systemic anti-tumor immunity. Thus, by more effectively delivering SD-101 to PDAC tumors and eliminating suppressive immune cells (e.g., MDSCs), a higher CPI responsiveness in locally advanced PDAC patients is possible.

The combination process can be performed in two stages, stage 1 and stage 1 b. In this regard, the primary purpose of stage 1 is to determine the Maximum Tolerated Dose (MTD) of SD 101 alone by PEDD/PRVI. Furthermore, a secondary objective is to evaluate the Response Evaluation Criterion (RECIST) v1.1 total response rate (ORR) of solid tumors. Regarding stage 1b, the main objective was to determine the safety of SD-101 combined administration with pembrolizumab via PEDD/PRVI and evaluate the response assessment criteria (RECIST) v1.1 total response rate (ORR) and 12 month Progression Free Survival (PFS) of solid tumors (common primary endpoint). Furthermore, a secondary objective was to evaluate the 12 month Overall Survival (OS) and progression free survival of PEDD/PRVI in combination with Intravenous (IV) immune checkpoint blockade of SD-101. In addition, another secondary objective was to evaluate the primary efficacy of RECIST on immune-based therapies (irec) ORR, RECIST 1.1 pancreas-specific response rate (PRR), duration of response (DOR), and clinical benefit (complete response [ CR ] + partial response [ PR ] + stable disease [ SD ]).

The overall design of the study can be seen in fig. 11.

In stage 1, increasing doses of SD-101 were administered alone by PEDD/PRVI into regional blood vessels of the pancreas containing locally advanced tumors. After determining the recommended MTD or optimal dose of SD-101 for PEDD/PRVI, the study may proceed to stage 1b to evaluate the safety and primary efficacy of simultaneous SD-101 and CPI use. Patients at stage 1b may receive a dose of SD-101 selected from stage 1 in the presence of a systemic anti-PD-1 checkpoint blockade. SD-101 may be administered in 2 cycles of 1 dose each with one month intervals.

After infusion of SD-101 to each patient at stage 1, either stay in hospital observation or admission therapy may be required. If the safety of SD-101PEDD/PRVI is established at stage 1, an overnight observation at stage 1b is at the discretion of the attending physician whether a subsequent SD-101 infusion will be made. If the infusion is on an outpatient basis, the patient may be observed at least 6 hours after the infusion prior to discharge if the clinical situation is stable. If hospitalization is required after the first infusion for any >2 event associated with SD-101PEDD/PRVI, the patient may be observed or hospitalized overnight after each SD-101 infusion.

Criteria for inclusion

According to one embodiment, for an enrollment study, the patient must meet all of the following enrollment criteria:

1. according to recistv1.1 standard, patients aged 18 or more years and with measurable or measurable locally advanced unresectable PDACs are confirmed histologically or cytologically. There is a need for focused imaging validation of NCCN-defined unresectable disease.

2. The eastern tumor cooperative group (ECOG) scale has a physical status score of 0 or 1 (score ranging from 0 to 5, with higher numbers indicating more severe disability)

Appropriate venous anatomy on ct intravenous imaging, defined as no portal vein, splenic vein or total occlusion of superior mesenteric vein.

4. Standard care chemo-or systemic chemotherapy regimens were received without complete radiological response. Standard care chemotherapy includes gemcitabine + albumin conjugated paclitaxel or FOLFIRINOX; other matters please discuss with the medical guardian. Radiation with or without chemotherapy may also be accepted as a standard of care regimen.

5. Adequate blood and organ function.

6. Can understand the study and provide written informed consent prior to any study procedure

7. No prior cytotoxic chemotherapy, targeted therapy or external radiation therapy was received within 14 days prior to screening

8. No prior history of malignancy or other concurrent malignancy, no ongoing treatment is required unless malignancy is clinically insignificant, and the patient is clinically stable

9. According to RECIST v.1.1 standard, has measurable liver disease

10. According to the evaluation of the researchers, life expectancy at screening was >3 months

11. With QTc interval less than or equal to 480 milliseconds

12. Prior to study treatment administration, all clinically significant (at the discretion of the investigator) drug-related toxicities (grade 2 alopecia and endocrinopathy allowing for alternative treatment control) associated with prior cancer therapies must be alleviated (to +.1 or patient pre-treatment levels).

13. Screening had sufficient organ function as evidenced by the following:

platelet count > 100,000/. Mu.L

Hemoglobin of 8.0g/dL or more

White blood cell count (WBC) >2,000/. Mu.L

Serum creatinine is less than or equal to 2.0mg/dL, except that the measured creatinine clearance is greater than or equal to 30 ml/min, as calculated by the formula of Kerrofil-Gao Erte.

Total bilirubin and direct bilirubin are less than or equal to 2.0×upper normal limit (ULN) and alkaline phosphatase is less than or equal to 5×ULN. For patients with recorded Gilbert's disease, total bilirubin is allowed to be as high as 3.0mg/dL.

ALT and AST.ltoreq.5XULN

Amylase and lipase +.ltoreq.3XULN

Prothrombin time/International Normalized Ratio (INR) or activated partial thromboplastin time (aPTT) assay at screening was 1.5 XULN (applicable only to patients not receiving anticoagulant therapy; patients receiving anticoagulant therapy should be dosed steadily for at least 4 weeks prior to the first dose of study intervention)

14. Women with fertility must be non-pregnant and non-lactating women or postmenopausal and the result of the serum human chorionic gonadotrophin (hCG) pregnancy test at screening and prior to the first dose of study intervention is negative.

Women with fertility must agree to avoid sexual behaviour with the non-sterile male partner during the whole study period, or if sexual behaviour with the non-sterile male partner must agree to use an efficient contraceptive method from screening and agree to continue to use such precautions for 100 days after the last dose of study.

Non-sterile men with fertility female-originating behaviour must agree to use an effective contraceptive method and avoid donation of sperm for the 1 st day of the entire study and 30 days after the last dose of study.

Stage 1

PEDD/PRVI dose escalation cohort using standard 3+3 design SD 101 monotherapy (2 cycles, 1 month interval):

dose level 1:0.5mg (n=3 to 6)

Dose level 2:2mg (n=3 to 6)

Dose level 3:4mg (n=3 to 6)

Dose level 4: 8mg (n=3 to 6)

Dose level 5 x 12mg (n=3 to 6)

* Dosage levels 4 and 5 are optional. If the PEDD/PRVI procedure and dosage levels 1 to 3 are well tolerated, but clinical and/or immune activity is minimal, additional dosage levels may be added. Clinical activity is defined as >20% reduction in SUV levels on FDG-PET scans for at least two patients or >20% reduction in serum CA-19-9 levels for at least two patients across dose levels of more than 1 RECIST 1.1CR or PR. The minimal immune response will be defined as no decrease in intratumoral MDSC, no increase in intratumoral cd8+ T cells or no increase in ifnα/ifnγ -associated gene signature.

The first 2 patients of each dose level may be staggered in groups for at least 72 hours. Progression to higher dose levels may be delayed by 7 days after the last infusion of the last subject at the previous dose level. After reviewing the safety data and confirmation by the SRC, it may progress to the next dose queue. An optional extension group of 10 patients at SD-101 monotherapy MTD or optimal dose can be performed simultaneously with stage 1 b.

Stage 1b

The standard 3+3 designed dose of PEDD/PRVI for SD-101 was re-incremented (2 cycles, 1 dose per cycle, one month interval) while 200mg of pembrolizumab was Intravenously (IV) every 3 weeks (Q3W) to identify the MTD or optimal dose of SD-101 via PEDD/PRVI by systemic CPI:

dose level 1: pembrolizumab is administered in combination with PEDD/PRVI of SD-101 at a dose level of 1 lower than the MTD or optimal dose of phase 1 (i.e., MTD-1 or optimal dose-1) (n=3 to 6)

Dose level 2: PEDD/PRVI combination of pembrolizumab and SD-101 at the MTD or optimal dose of phase 1 (n=3 to 6), or if MTD-1 or optimal dose-1 is intolerant, the dose is decremented to MTD-2 or optimal dose-2

The first 2 patients of each dose level may be staggered in groups for at least 48 hours. Progression to higher dose levels may be delayed by 7 days after the last infusion of the last subject at the previous dose level. After reviewing the safety data and confirmation by the SRC, it may progress to the next dose queue. An optional extension group of 10 to 20 patients with MTD or optimal dose may be performed.

There will be an optional expansion queue on either RP2D of SD-101 in combination with pembrolizumab or RP2D of SD-101 in combination with nivolumab+ipilimumab.

Research intervention

TABLE 17

* The unit dose intensity of SD-101 reflects only SD-101 oligomer.

Abbreviations: IMP = study drug; IV = intravenous; NIMP = non-study drug.

SD-101 administration

SD-101 may be administered using a SEAL device. The SEAL device is a 5.0F to 3.1F tapered coaxial infusion catheter with a 0.021 "lumen with an expandable valve at the distal end for use as a catheter for physician prescribed medications. The valve is designed to expand to varying degrees within a vessel of 2 to 6mm diameter and form a fluid impermeable barrier in the case of retrograde flow. The device is also adapted to be connected to standard Invasive Blood Pressure (IBP) sensors, allowing continuous pressure monitoring of the vasculature distal to the valve throughout the therapeutic drug infusion process. During infusion, the device blocks all retrograde flow and creates pressure in the blood vessel, resulting in perfusion of the venous and capillary networks isolated by the device.

CPI management

Pembrolizumab, nivolumab, and ipilimumab can be administered by IV infusion at the dose levels specified in table 12, respectively.

Duration of SD-101 dosing (all participants in phase 1 and phase 1 b)

Up to 2 doses (over 2 cycles, each cycle being separated by a month). The second cycle of SD-101 may be omitted based on toxicity or tolerance. All patients receiving at least 1 dose of PEDD/PRVI of SD-101 will be considered to be evaluable.

Duration of CPI administration

Pembrolizumab 200mg q3w up to 6 months.

PEDD/PRVI of SD-101

SD 101 solution can be infused through the pancreatic venous system using a SEAL device. Briefly, the method involves performing a transhepatic or transjugular imaging to define a target draining pancreatic vein that will allow selective drug delivery to the tumor-containing gland region. In some cases, one vein may be sufficient, while in other cases drug delivery via 2 or more branches may be required. Off-target branching may require embolic occlusion.

SD-101 treatment volume: 10mL

SD-101 therapeutic dose: 0.5mg,2mg,4mg

SD-101 diluent: commercially available, preservative free, 0.9% sodium chloride, USP (sterile isotonic saline).

Tumor response assessment

All patients can be imaged with Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) to assess the extent of pancreatic disease and metabolic activity, as well as any extrapancreatic lesions, pancreatic biopsies and CTCs, circulating cytokines and other immune-related factor assays. Tumor response can be measured by radiological imaging using standard recistvl.1 standard. A preliminary assessment of the formal response score (according to RECIST v 1.1) may be made 21 days after each infusion. The final response score may be determined 42 days after the second infusion to ensure that false progress is eliminated and the initial response is confirmed. The imaging process may be performed every 90 days thereafter. The local imaging readings can be used for response assessment during phase 1. During stage 1b, a separate central review of the response assessment may be performed.

Up to 2 PDAC tumor core needle biopsies were performed by Endoscopic Ultrasound (EUS):

baseline biopsies were obtained one week prior to the first infusion of SD-101

A second biopsy will be taken one week after the second cycle of SD-101 (before SD-101 infusion # 2).

During each biopsy, 3 core needle samples will be collected from PDAC tumors under EUS guidance.

The pathology response will be assessed based on a pathologist's review of the clinical trial institution and the scores for necrosis and fibrosis within the tumor samples. If multiple clinical trial institutions are involved in the study, pathology review will be focused on a single clinical trial institution.

Will follow the protocol for an immunologically relevant study

Intravascular pressure recordings will be obtained during each infusion.

Pharmacokinetics of

After PEDD/PRVI, blood samples can be collected to characterize SD-101 systemic exposure. The CPI concentration will not be sampled or tested. Tumor levels of SD-101 can be measured in biopsy samples after infusion.

Pharmacodynamics of medicine

Blood samples may be collected for measurement of CTCs, circulating cytokines and other immune-related factors, including interferon alpha (IFN- α) and interferon gamma (IFN- γ) related gene signatures, which may be more informative than Pharmacokinetic (PK) assessment of such therapeutic agents.

Safety of

For phases 1 and 1b, SRCs composed of researchers may be used to ensure patient safety, determine dose queue transitions, decide whether to continue or terminate the study prematurely, and oversee study behavior and data validity and integrity. Membership may vary depending on the stage of the study. A statistical staff may be included during the phase 1b part of the study.

Safety assessments include clinically indicated Adverse Events (AEs), clinical laboratory tests, vital signs, physical examinations, and Electrocardiography (ECG).

The following observed during the SD-101 cycle or within 2 weeks after the last SD-101 dose of cycle 2 is considered DLT and is considered attributable to study intervention (SD-101 or CPI therapy) and/or PEDD device:

grade 3 Cytokine Release Syndrome (CRS) according to the National Cancer Institute (NCI) adverse event common terminology standard (CTCAE)

According to NCI CTCAE, autoimmune AE is not less than grade 3

According to NCI CTCAE, the allergic reaction AE is not less than grade 3

According to NCI CTCAE, grade 4 hematological AE did not recover to grade 2 or less within 7 days

NCI CTCAE of any organ system (including pancreatitis) grade 4 AE

Patients who develop DLT during either period of SD 101 may permanently stop study intervention unless sufficient reasons are provided to prove that alternative methods (e.g., modified doses) are reasonably safe at a particular DLT. Patients can be treated and monitored for regression of toxicity according to clinical practice.

SD-101 and/or CPI therapy may be permanently discontinued due to serious or life threatening infusion-related reactions. When patients develop a grade 3 or higher immune-mediated response, the SD-101 and/or CPI therapy needs to be discontinued, delayed or discontinued. The SD-101 and/or CPI therapy may need to be discontinued when the patient meets one of the following conditions:

clinical or imaging evidence of severe pancreatitis in patients

Clinical evidence of portal hypertension in patients, including but not limited to moderate or severe ascites or variceal bleeding of clinical significance.

In some embodiments, the invention relates to the use of a TLR9 agonist in the manufacture of a medicament for treating a solid tumor in the pancreas, the method comprising administering the TLR9 agonist to a patient in need thereof, wherein the TLR9 agonist is administered to such solid tumor in the pancreas by means of a device in the manner of PRVI.

The foregoing merely illustrates the principles of the disclosure. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements and procedures which, although not explicitly shown or described herein, embody the principles of the disclosure and are thus within the spirit and scope of the present disclosure. Those of ordinary skill in the art will appreciate that the various exemplary embodiments may be used with each other or interchangeably. In addition, certain terms used in this disclosure, including the description, may be used synonymously in certain circumstances, including, but not limited to, data and information, for example. It should be understood that although these terms and/or other terms that may be synonymous with each other may be used synonymously herein, there may be circumstances where these terms may not be intended to be synonymously used. Furthermore, to the extent that the prior art knowledge described above is not explicitly incorporated herein by reference, it is explicitly incorporated herein in its entirety. All publications referred to are incorporated herein by reference in their entirety.

Sequence listing

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<120> cancer therapy Using toll-like receptor agonists

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Claims

1. A method for treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a toll-like receptor 9 agonist having the structure: 5'-TCG AAC GTT CGA ACG TTC GAA CGT TCG AAT-3' (SEQ ID NO: 1).

2. The method of claim 1, wherein the TLR9 agonist is administered by means of a device as a Pancreatic Retrograde Venous Infusion (PRVI).

3. The method of claim 1, wherein the TLR9 agonist is administered at a concentration selected from the group consisting of 0.5mg, 2mg, 4mg, 8mg, or 12 mg.

4. The method of claim 2, wherein the TLR9 agonist is capable of being administered through a catheter device.

5. The method of claim 4, wherein the catheter device is a temporary occlusion device.

6. The method of claim 2, wherein the TLR9 agonist is administered via pressure-enabled drug delivery through the catheter device.

7. The method of claim 7, wherein the TLR9 agonist is administered at an infusion rate of about 1 ml/min to about 10 ml/min.

8. The method of claim 7, wherein the TLR9 agonist is administered for a period of 2 to 20 minutes.

9. The method of claim 1, wherein the TLR9 agonist is administered in combination with one or more checkpoint inhibitors, wherein the checkpoint inhibitor is administered systemically at the same time, before or after administration of the TLR9 agonist.

10. The method of claim 10, wherein the one or more checkpoint inhibitors comprise at least one of nivolumab (nivolumab), pembrolizumab (pembrolizumab), and cemipramiab (cemiplimab), atilizumab (atezolizumab), avistuzumab (avelumab), and devaluzumab (durvalumab) and ipilimumab (ipilimumaab).

11. The method of claim 1, wherein the administration of the TLR9 agonist comprises a dosing regimen comprising a cycle, wherein one or more of the cycles comprises administration of the TLR9 agonist via a catheter device by Pancreatic Retrograde Venous Infusion (PRVI) followed by systemic administration of a checkpoint inhibitor.

12. The method of claim 10, wherein the one or more checkpoint inhibitors comprise at least one of nivolumab, pembrolizumab, and cimetidine Li Shan antibody, atilizumab, avermectin, and Dewaruzumab, and ipilimumab.